Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscle cells express a distinct splice variant of acetylcholinesterase (AChE(T)), but the specific mechanisms governing this restricted expression remain unclear. In these cells, a fraction of AChE subunits is associated with a triple helical collagen, ColQ, each strand of which can recruit a tetramer of AChE(T). In the present study, we examined the expression of the various splice variants of AChE by transfection in the mouse C2C12 myogenic cells in vitro, as well as in vivo by injecting plasmid DNA directly into tibialis anterior muscles of mice and rats. Surprisingly, we found that transfection with an ACHE(H) cDNA, generating a glycophosphatidylinositol-anchored enzyme species, produced much more activity than transfection with AChE(T) cDNA in both C2C12 cells and in vivo. This indicates that the exclusive expression of AChE(T) in mature muscle is governed by specific splicing. Interaction of AChE(T) subunits with the complete collagen tail ColQ increased enzyme activity in cultured cells, as well as in muscle fibers in vivo. Truncated ColQ subunits, presenting more or less extensive C-terminal deletions, also increased AChE activity and secretion in C2C12 cells, although the triple helix could not form in the case of the larger deletion. This suggests that heteromeric associations are stabilized compared with isolated AChE(T) subunits. Coinjections of AChE(T) and ColQ resulted in the production and secretion of asymmetric forms, indicating that assembly, processing, and externalization of these molecules can occur outside the junctional region of muscle fibers and hence does not require the specialized junctional Golgi apparatus.
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PMID:Stability and secretion of acetylcholinesterase forms in skeletal muscle cells. 1049 26

The end-plate species of acetylcholinesterase (AChE) is an asymmetric enzyme consisting of a collagenic tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of the T isoform of the catalytic subunit (AChE(T)) via a proline-rich attachment domain. The principal function of the tail subunit is to anchor asymmetric AChE in the synaptic basal lamina. Human end-plate AChE deficiency was recently shown to be caused by mutations in COLQ. We here report nine novel COLQ mutations in 7 patients with end-plate AChE deficiency. We examine the effects of the mutations on the assembly of asymmetric AChE by coexpressing each genetically engineered COLQ mutant with ACHE(T) in COS cells. We classify the newly recognized and previously reported COLQ mutations into four classes according to their position in ColQ and their effect on AChE expression. We find that missense mutations in the proline-rich attachment domain abrogate attachment of catalytic subunits, that truncation mutations in the ColQ collagen domain prevent the assembly of asymmetric AChE, that hydrophobic missense residues in the C-terminal domain prevent triple helical assembly of the ColQ collagen domain, and that other mutations in the C-terminal region produce asymmetric species of AChE that are likely insertion incompetent.
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PMID:The spectrum of mutations causing end-plate acetylcholinesterase deficiency. 1066 86

Hypersensitivity to acetylcholinesterase inhibitors (anti-AChEs) causes severe nervous system symptoms under low dose exposure. In search of direct genetic origin(s) for this sensitivity, we studied six regions in the extended 22 kb promoter of the ACHE gene in individuals who presented adverse responses to anti-AChEs and in randomly chosen controls. Two contiguous mutations, a T-->A substitution, disrupting a putative glucocorticoid response element, and a 4-bp deletion, abolishing one of two adjacent HNF3 binding sites, were identified 17 kb upstream of the transcription start site. Allele frequencies for these mutations were 0.006 and 0.012, respectively, in 333 individuals of various ethnic origins, with a strong linkage between the deletion and the biochemically neutral H322N mutation in the coding region of ACHE. Heterozygous carriers of the deletion included a proband who presented with acute hypersensitivity to the anti-AChE pyridostigmine and another with unexplained excessive vomiting during a fourth pregnancy following three spontaneous abortions. Electromobility shift assays, transfection studies and measurements of AChE levels in immortalized lymphocytes as well as in peripheral blood from both carriers and non-carriers, revealed functional relevance for this mutation both in vitro and in vivo and showed it to increase AChE expression, probably by alleviating competition between the two hepatocyte nuclear factor 3 binding sites. Moreover, AChE-overexpressing transgenic mice, unlike normal FVB/N mice, displayed anti-AChE hypersensitivity and failed to transcriptionally induce AChE production following exposure to anti-AChEs. Our findings point to promoter polymorphism(s) in the ACHE gene as the dominant susceptibility factor(s) for adverse responses to exposure or to treatment with anti-AChEs.
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PMID:A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases. 1081 9

Acetylcholinesterase (AChE; EC 3.1.1.7) is the primary terminator of nerve impulse transmission at cholinergic synapses and is believed to play an important role in neural development. Targeted deletion of four exons of the ACHE gene reduced AChE activity by half in heterozygous mutant mice and totally eliminated AChE activity in nullizygous animals. Butyrylcholinesterase (EC 3.1.1.8) activity was normal in AChE -/- mice. Although nullizygous mice were born alive and lived up to 21 days, physical development was delayed. The neuromuscular junction of 12-day-old nullizygous animals appeared normal in structure. Nullizygous mice were highly sensitive to the toxic effects of the organophosphate diisopropylfluorophosphate and to the butyrylcholinesterase-specific inhibitor bambuterol. These findings indicate that butyrylcholinesterase and possibly other enzymes are capable of compensating for some functions of AChE and that the inhibition of targets other than AChE by organophosphorus agents results in death.
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PMID:Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. 1086 90

Cat serum contains 0.5 mg/L of butyrylcholinesterase (BChE, EC 3.1.1. 8) and 0.3 mg/L of acetylcholinesterase (AChE, EC 3.1.1.7); this can be compared with 5 mg/mL and < 0.01 mg/L, respectively, in human serum. Cat BChE differed from human BChE in the steady-state turnover of butyrylthiocholine, having a 3-fold higher k(cat) and 2-fold higher K(m) and K(ss) values. Sequencing of the cat BCHE cDNA revealed 70 amino acid differences between cat and human BChE, three of which could account for these kinetic differences. These amino acids, which were located in the region of the active site, were Phe398Ile, Pro285Leu, and Ala277Leu (where the first amino acid was found in human and the second in cat). Sequencing genomic DNA for cat and human ACHE demonstrated that there were 33 amino acid differences between the cat and human AChE enzymes, but that there were no differences in the active site region. In addition, a polymorphism in intron 3 of the human ACHE gene was detected, as well as a silent polymorphism at Y116 of the cat ACHE gene.
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PMID:Determination of the DNA sequences of acetylcholinesterase and butyrylcholinesterase from cat and demonstration of the existence of both in cat plasma. 1087 22

Rheological and enzymatic properties of red blood cells (RBC) were investigated in vitro after the treatment with vasoactive drug - buflomedil (bfl) and toxic substance - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies with bfl included two different concentrations of the drug: 90 microg/ml of blood and 10 microg/ml of blood. The former concentration of the drug corresponds to the amount of bfl which is taken daily by a patient, the latter one is the highest peak of this drug in plasma. The dosage of dioxin was 32 microg/ml of blood and 32 ng/ml of blood. Only the smaller dosage of this compound appears in the environment but the higher one may occur in human organs because of its cumulation. Rheological properties of erythrocytes were examined using a laser diffractometer Rheodyne SSD (Myrenne). The deformability of RBC was expressed as an elongation index IE which was counted from the equation: EI=(L-W)/(L+W) where L is the length of cell and W is the width of cell. As far as the impact of bfl on RBC rheology is concerned studies were conducted in two different ways: (1) RBC were incubated with bfl directly, (2) RBC before incubation with bfl were treated with diamide to cause their rigidity. The action of bfl seems to be not efficient enough as data are not statistically significant in those two cases. Enzymatic properties of RBC were investigated using the methods of Beutler [7]. The activity of three enzymes was measured (acetylcholinesterase - Ache, dehydrogenase glucoso-6-phosphate - G-6-PD and gluthatione reductase - GR) for both bfl and TCDD-treated RBC. For TCDD-treated RBC additionally malonyldialdehyde (MDA) level was assessed.
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PMID:Rheological and biochemical examination of red blood cells after treatment with different pharmacological and toxic substances. 1208 57

We report the case of an 81-year-old woman, suffering from a major depressive episode and incipient Alzheimer disease, whom we treated with ECT without interrupting therapy with the acetylcholinesterase inhibitor (ACHE-I) rivastigmine. After eight right unilateral ECT sessions, the patient remitted completely without any significant deterioration of memory and cognitive abilities or cholinergic side effects. This report demonstrates that ECT was safely used in one elderly and mildly demented person with continuous ACHE-I therapy. The hypothesis that this drug may indeed protect against unfavorable side effects of ECT should be further tested in clinical trials.
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PMID:Electroconvulsive therapy in a patient receiving rivastigmine. 1239 36

To study the regulation of acetylcholinesterase (AChE) gene expression in human brain tumors, 3' splice variants of AChE mRNA and potentially relevant transcription factor mRNAs were labeled in primary astrocytomas and melanomas. AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in correlation with tumor aggressiveness, but neither HNF3beta nor c-fos mRNA was observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and not the secreted AChE-R variant, was retained in astrocyte tumor cells. Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE gene expression in co-transfected COS1 cells. The p300 co-activator and the ACHE promoter's distal enhancer facilitated this effect, which was independent of much of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product of green fluorescence protein (GFP) and ASP(67), a peptide composed of the 67 C-terminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However, GARP, the corresponding fusion product of GFP with a peptide having the 51 C-terminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1 exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting modulated nuclear localization processes. Together, these findings reveal brain tumor-specific regulation of both expression and cellular retention of variant ACHE gene products.
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PMID:Complex regulation of acetylcholinesterase gene expression in human brain tumors. 1246 63

Per (3,6-anhydro-2-O-carboxymethyle) alpha-cyclodextrin ([ACX]) is a polydentate analog of EDTA, a well-known cation chelating reagent. ACX exhibits strong affinities in vitro for uranyl, cobalt and also for lanthanids such as Europium and Cerium. The hydrolytic activities of ACX-Eu and ACX-Ce complex were directly tested on an organophosphorous compound: the neurotoxic Soman (GD), an inhibitor of acetylcholinesterase (ACHE from rat brain). It was found a three fold reduction of soman activity when measured in the presence of Ce-ACX complex. Conversely, Eu-ACX effect did not result in soman inhibition variation under physiological conditions. It is suggested that, considering usual organometallic complex of cyclodextrin, such direct complexes would be of interest in the design of pseudo-enzyme systems for phosphoester hydrolysis.
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PMID:Hydrolytic properties of per (3,6-anhydro, 2-O-carboxymethyl) alpha cyclodextrin complexes of Ce (III) and Eu (III): application to soman (GD) degradation. 1280 27

To determine whether the efficacy of entry and action of antisense oligonucleotides (AS-ODN) on hematopoietic stem cells in vitro could be improved by the addition of polyethylene glycol (PEG), a molecule of PEG was bound to AS- or sense-acetylcholinesterase (AS-ACHE or S-ACHE). The introduction of 0.1-0.5 microM PEG-AS-ACHE or 0.5 microM AS-ACHE into methylcellulose bone marrow (BM) cultures produced a doubling in number of colony-forming unit-granulocyte-erythrocyte-macrophage-megakaryocyte (CFU-GEMM) and a 5-fold increase in cell number of the PEG-ODN. Further increase in concentration of the PEG-ODN reduced colony numbers. PEG-AS-ACHE induced higher colony numbers and greatly increased megakaryocyte (MK) formation when compared with PEG and AS-ACHE added separately to the culture. In addition, differentials of the CFU-GEMMs indicated there was a direct relationship between MK number and PEG-AS-ACHE concentration. Under these culture conditions, 5 microM PEG alone gave control values of CFU-GEMM. On addition of FITC-PEG-AS-ACHE to the cell cultures, using confocal microscopy, the nuclei of both early and mature MKs were labeled specifically, whereas all other cellular nuclei were negative to the stain. The use of PEG-AS-ODN, affording specific delivery of AS-ODN to target cells, increased cell proliferation, and enhanced ODN uptake, may be of potential importance in stem cell expansion for BM transplantation and gene therapy.
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PMID:The effect of pegylated antisense acetylcholinesterase on hematopoiesis. 1500 Aug 36


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